NM_004004.6(GJB2):c.551G>C (p.Arg184Pro) AND Nonsyndromic genetic hearing loss

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 31, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001257160.9

Allele description [Variation Report for NM_004004.6(GJB2):c.551G>C (p.Arg184Pro)]

NM_004004.6(GJB2):c.551G>C (p.Arg184Pro)

Gene:

GJB2:gap junction protein beta 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q12.11

Genomic location:

Preferred name:

NM_004004.6(GJB2):c.551G>C (p.Arg184Pro)

HGVS:

NC_000013.11:g.20189031C>G
NG_008358.1:g.8945G>C
NM_004004.6:c.551G>CMANE SELECT
NP_003995.2:p.Arg184Pro
LRG_1350t1:c.551G>C
LRG_1350:g.8945G>C
LRG_1350p1:p.Arg184Pro
NC_000013.10:g.20763170C>G
NM_004004.5:c.551G>C
P29033:p.Arg184Pro
c.551G>C
c.551G>C (p.Arg184Pro)

Protein change:

R184P; ARG184PRO

Links:

UniProtKB: P29033#VAR_015943; OMIM: 121011.0008; dbSNP: rs80338950

NCBI 1000 Genomes Browser:

rs80338950

Molecular consequence:

NM_004004.6:c.551G>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

Observations:

Condition(s)

Name:: Nonsyndromic genetic hearing loss
Synonyms:: Nonsyndromic hearing loss and deafness; Non-syndromic genetic deafness; Nonsyndromic genetic deafness
Identifiers:: MONDO: MONDO:0019497; MedGen: C5680182; Orphanet: 87884

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001433678	INGEBI, INGEBI / CONICET	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Pathogenic (Aug 31, 2020)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 24158611, 10874298, 10982180, 11551103, 12176179, 16380907, 17485979, 12176036, 1218943, 12505163, 30311386

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001433678

INGEBI, INGEBI / CONICET

criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)

Pathogenic
(Aug 31, 2020)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
Caucasian	germline	yes	4	4	not provided	not provided	no	clinical testing

Citations

PubMed

Identification of four novel connexin 26 mutations in non-syndromic deaf patients: genotype-phenotype analysis in moderate cases.

Dalamón V, Florencia Wernert M, Lotersztein V, Craig PO, Diamante RR, Barteik ME, Curet C, Paoli B, Mansilla E, Elgoyhen AB.

Mol Biol Rep. 2013 Dec;40(12):6945-55. doi: 10.1007/s11033-013-2814-x. Epub 2013 Oct 25.

PubMed [citation]

PMID:: 24158611

Mutation analysis of the GJB2 (connexin 26) gene by DGGE in Greek patients with sensorineural deafness.

Antoniadi T, Grønskov K, Sand A, Pampanos A, Brøndum-Nielsen K, Petersen MB.

Hum Mutat. 2000;16(1):7-12.

PubMed [citation]

PMID:: 10874298

See all PubMed Citations (11)

Details of each submission

From INGEBI, INGEBI / CONICET, SCV001433678.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	4	not provided	no	clinical testing	PubMed (11)

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filter allele frequency of c.551G>C, p.Arg184Pro variant in GJB2 gene is 0,0038% (4/35426 Latino alleles with 95% CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the PM2 criteria. This variant was identified at least in five individuals in trans with several known pathogenic variants (PM3_VeryStrong; PMID: 24158611, 10874298, 10982180, 11551103, 12176179, 16380907, 16380907, 17485979). Computational evidence predicted a damage impact of the mutation to the protein meeting PP3 rule (REVELscore: 0,983) Functional studies demonstrated that: mutant protein is neither trafficked to membrane nor able to oligomerize efficiently and unable to form functional GJCh in HeLa cells (PMID: 12176036, 1218943). Moreover, p.Arg184Pro mutant did not induce the formation of homotypic junctional channels, since the levels of conductance measured never exceeded background values in Xenopus laevis oocytes (PMID: 12505163), PS3_Moderate Therefore, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2, PM3_VeryStrong, PP3 and PS3_Moderate).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	blood	not provided		4	not provided	4	not provided

Last Updated: May 1, 2024

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